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Erschienen in: Cancer Chemotherapy and Pharmacology 5/2009

01.04.2009 | Original Article

The polymorphisms of TS and MTHFR predict survival of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population

verfasst von: Zhao-Hui Huang, Dong Hua, Li-Hua Li

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2009

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Abstract

Purpose

The aim of this study was to investigate the association of the thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms with the clinical outcomes of gastric cancer patients treated with 5-FU-based adjuvant chemotherapy.

Methods

One-hundred and sixteen patients with gastric cancer were treated with 5-FU-based adjuvant chemotherapy. The TS (a 28-bp tandem repeat polymorphism in the TS enhancer region (TSER) and a 6 bp deletion/insertion polymorphism in the 3′-untranslated region) and MTHFR C677T polymorphisms were determined in blood samples from those patients using PCR and PCR-LDR (ligation detection reaction) method, respectively.

Results

The overall survival (OS) in patients with the TS ins6/ins6 genotype was significantly shorter than those in patients with the del6/del6 (= 0.017) and ins6/del6 (= 0.022) genotype. The relapse-free survival (RFS) and OS in patients with the MTHFR C/C genotype were significantly worse than those in patients with the T/T or C/T genotype (= 0.043 and 0.040, respectively). Cox multivariate analysis also showed that patients with the TS ins6/ins6 genotype have worse OS than patients with the T/T or C/T genotype (HR = 2.437, = 0.041), and the MTHFR C/C genotype was associated with shorter RFS (HR = 1.723, = 0.031) and OS (HR = 1.681, = 0.056). No significant association was found between the TSER polymorphism and the clinical outcomes (> 0.05).

Conclusion

The polymorphisms of TS 3′-UTR ins6/del6 and MTHFR C677T appear to be potential prognostic factors in gastric cancer patients treated with 5-FU-based adjuvant chemotherapy, which may allow identification of gastric cancer patients who will benefit from 5-FU chemotherapy.
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Literatur
2.
Zurück zum Zitat Mari E, Floriani I, Tinazzi A, Buda A, Belfiglio M, Valentini M, Cascinu S, Barni S, Labianca R, Torri V (2000) Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 11:837–843PubMedCrossRef Mari E, Floriani I, Tinazzi A, Buda A, Belfiglio M, Valentini M, Cascinu S, Barni S, Labianca R, Torri V (2000) Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 11:837–843PubMedCrossRef
3.
Zurück zum Zitat Hejna M, Wohrer S, Schmidinger M, Raderer M (2006) Postoperative chemotherapy for gastric cancer. Oncologist 11:136–145PubMedCrossRef Hejna M, Wohrer S, Schmidinger M, Raderer M (2006) Postoperative chemotherapy for gastric cancer. Oncologist 11:136–145PubMedCrossRef
4.
Zurück zum Zitat Carrato A, Gallego-Plazas J, Guillen-Ponce C (2005) Adjuvant therapy of resected gastric cancer is necessary. Semin Oncol 32:S105–S108PubMedCrossRef Carrato A, Gallego-Plazas J, Guillen-Ponce C (2005) Adjuvant therapy of resected gastric cancer is necessary. Semin Oncol 32:S105–S108PubMedCrossRef
5.
Zurück zum Zitat Ishida Y, Kawakami K, Tanaka Y, Kanehira E, Omura K, Watanabe G (2002) Association of thymidylate synthase gene polymorphism with its mRNA and protein expression and with prognosis in gastric cancer. Anticancer Res 22:2805–2809PubMed Ishida Y, Kawakami K, Tanaka Y, Kanehira E, Omura K, Watanabe G (2002) Association of thymidylate synthase gene polymorphism with its mRNA and protein expression and with prognosis in gastric cancer. Anticancer Res 22:2805–2809PubMed
6.
Zurück zum Zitat Goekkurt E, Hoehn S, Wolschke C, Wittmer C, Stueber C, Hossfeld DK, Stoehlmacher J (2006) Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)–novel predictors for response and survival in gastric cancer patients. Br J Cancer 94:281–286PubMedCrossRef Goekkurt E, Hoehn S, Wolschke C, Wittmer C, Stueber C, Hossfeld DK, Stoehlmacher J (2006) Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)–novel predictors for response and survival in gastric cancer patients. Br J Cancer 94:281–286PubMedCrossRef
7.
Zurück zum Zitat Ott K, Vogelsang H, Marton N, Becker K, Lordick F, Kobl M, Schuhmacher C, Novotny A, Mueller J, Fink U, Ulm K, Siewert JR, Hofler H, Keller G (2006) The thymidylate synthase tandem repeat promoter polymorphism: a predictor for tumor-related survival in neoadjuvant treated locally advanced gastric cancer. Int J Cancer 119:2885–2894PubMedCrossRef Ott K, Vogelsang H, Marton N, Becker K, Lordick F, Kobl M, Schuhmacher C, Novotny A, Mueller J, Fink U, Ulm K, Siewert JR, Hofler H, Keller G (2006) The thymidylate synthase tandem repeat promoter polymorphism: a predictor for tumor-related survival in neoadjuvant treated locally advanced gastric cancer. Int J Cancer 119:2885–2894PubMedCrossRef
8.
Zurück zum Zitat Park DJ, Lenz HJ (2006) Determinants of chemosensitivity in gastric cancer. Curr Opin Pharmacol 6:337–344PubMedCrossRef Park DJ, Lenz HJ (2006) Determinants of chemosensitivity in gastric cancer. Curr Opin Pharmacol 6:337–344PubMedCrossRef
9.
Zurück zum Zitat Hua D, Huang ZH, Mao Y, Deng JZ (2007) Thymidylate synthase and thymidine phosphorylase gene expression as predictive parameters for the efficacy of 5-fluorouracil-based adjuvant chemotherapy for gastric cancer. World J Gastroenterol 13:5030–5034PubMed Hua D, Huang ZH, Mao Y, Deng JZ (2007) Thymidylate synthase and thymidine phosphorylase gene expression as predictive parameters for the efficacy of 5-fluorouracil-based adjuvant chemotherapy for gastric cancer. World J Gastroenterol 13:5030–5034PubMed
10.
Zurück zum Zitat Wei J, Zou Z, Qian X, Ding Y, Xie L, Sanchez JJ, Zhao Y, Feng J, Ling Y, Liu Y, Yu L, Rosell R, Liu B (2008) ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen. Br J Cancer 98:1398–1402PubMedCrossRef Wei J, Zou Z, Qian X, Ding Y, Xie L, Sanchez JJ, Zhao Y, Feng J, Ling Y, Liu Y, Yu L, Rosell R, Liu B (2008) ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen. Br J Cancer 98:1398–1402PubMedCrossRef
11.
Zurück zum Zitat Kawakami K, Omura K, Kanehira E, Watanabe Y (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19:3249–3252PubMed Kawakami K, Omura K, Kanehira E, Watanabe Y (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19:3249–3252PubMed
12.
Zurück zum Zitat Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J, Omura K, Watanabe G, Danenberg PV (2001) Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 7:4096–4101PubMed Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J, Omura K, Watanabe G, Danenberg PV (2001) Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 7:4096–4101PubMed
13.
Zurück zum Zitat Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, Lenz HJ, Ladner RD (2004) A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14:319–327PubMedCrossRef Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, Lenz HJ, Ladner RD (2004) A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14:319–327PubMedCrossRef
14.
Zurück zum Zitat Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22:195–201PubMedCrossRef Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22:195–201PubMedCrossRef
15.
Zurück zum Zitat Sohn KJ, Croxford R, Yates Z, Lucock M, Kim YI (2004) Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 96:134–144PubMedCrossRef Sohn KJ, Croxford R, Yates Z, Lucock M, Kim YI (2004) Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 96:134–144PubMedCrossRef
16.
Zurück zum Zitat Cohen V, Panet-Raymond V, Sabbaghian N, Morin I, Batist G, Rozen R (2003) Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 9:1611–1615PubMed Cohen V, Panet-Raymond V, Sabbaghian N, Morin I, Batist G, Rozen R (2003) Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 9:1611–1615PubMed
17.
Zurück zum Zitat Jakobsen A, Nielsen JN, Gyldenkerne N, Lindeberg J (2005) Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 23:1365–1369PubMedCrossRef Jakobsen A, Nielsen JN, Gyldenkerne N, Lindeberg J (2005) Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 23:1365–1369PubMedCrossRef
18.
Zurück zum Zitat Ruzzo A, Graziano F, Kawakami K, Watanabe G, Santini D, Catalano V, Bisonni R, Canestrari E, Ficarelli R, Menichetti ET, Mari D, Testa E, Silva R, Vincenzi B, Giordani P, Cascinu S, Giustini L, Tonini G, Magnani M (2006) Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol 24:1883–1891PubMedCrossRef Ruzzo A, Graziano F, Kawakami K, Watanabe G, Santini D, Catalano V, Bisonni R, Canestrari E, Ficarelli R, Menichetti ET, Mari D, Testa E, Silva R, Vincenzi B, Giordani P, Cascinu S, Giustini L, Tonini G, Magnani M (2006) Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol 24:1883–1891PubMedCrossRef
19.
Zurück zum Zitat Pare L, Altes A, Ramon y Cajal T, Del Rio E, Alonso C, Sedano L, Barnadas A, Baiget M (2007) Influence of thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms on the disease-free survival of breast cancer patients receiving adjuvant 5-fluorouracil/methotrexate-based therapy. Anticancer Drugs 18:821–825PubMedCrossRef Pare L, Altes A, Ramon y Cajal T, Del Rio E, Alonso C, Sedano L, Barnadas A, Baiget M (2007) Influence of thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms on the disease-free survival of breast cancer patients receiving adjuvant 5-fluorouracil/methotrexate-based therapy. Anticancer Drugs 18:821–825PubMedCrossRef
20.
Zurück zum Zitat Huang ZH, Hua D, Li LH, Zhu JD (2008) Prognostic role of p53 codon 72 polymorphism in gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy. J Cancer Res Clin Oncol (in press) Huang ZH, Hua D, Li LH, Zhu JD (2008) Prognostic role of p53 codon 72 polymorphism in gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy. J Cancer Res Clin Oncol (in press)
21.
Zurück zum Zitat Iacopetta B, Grieu F, Joseph D, Elsaleh H (2001) A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 85:827–830PubMedCrossRef Iacopetta B, Grieu F, Joseph D, Elsaleh H (2001) A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 85:827–830PubMedCrossRef
22.
Zurück zum Zitat Martinez-Balibrea E, Manzano JL, Martinez-Cardus A, Moran T, Cirauqui B, Catot S, Taron M, Abad A (2007) Combined analysis of genetic polymorphisms in thymidylate synthase, uridine diphosphate glucoronosyltransferase and X-ray cross complementing factor 1 genes as a prognostic factor in advanced colorectal cancer patients treated with 5-fluorouracil plus oxaliplatin or irinotecan. Oncol Rep 17:637–645PubMed Martinez-Balibrea E, Manzano JL, Martinez-Cardus A, Moran T, Cirauqui B, Catot S, Taron M, Abad A (2007) Combined analysis of genetic polymorphisms in thymidylate synthase, uridine diphosphate glucoronosyltransferase and X-ray cross complementing factor 1 genes as a prognostic factor in advanced colorectal cancer patients treated with 5-fluorouracil plus oxaliplatin or irinotecan. Oncol Rep 17:637–645PubMed
23.
Zurück zum Zitat Lecomte T, Ferraz JM, Zinzindohoue F, Loriot MA, Tregouet DA, Landi B, Berger A, Cugnenc PH, Jian R, Beaune P, Laurent-Puig P (2004) Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res 10:5880–5888PubMedCrossRef Lecomte T, Ferraz JM, Zinzindohoue F, Loriot MA, Tregouet DA, Landi B, Berger A, Cugnenc PH, Jian R, Beaune P, Laurent-Puig P (2004) Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res 10:5880–5888PubMedCrossRef
24.
Zurück zum Zitat Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, Masi G, Schiavon G, Giordani P, Giustini L, Falcone A, Tonini G, Silva R, Mattioli R, Floriani I, Magnani M (2007) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 25:1247–1254PubMedCrossRef Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, Masi G, Schiavon G, Giordani P, Giustini L, Falcone A, Tonini G, Silva R, Mattioli R, Floriani I, Magnani M (2007) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 25:1247–1254PubMedCrossRef
25.
Zurück zum Zitat Dotor E, Cuatrecases M, Martinez-Iniesta M, Navarro M, Vilardell F, Guino E, Pareja L, Figueras A, Mollevi DG, Serrano T, de Oca J, Peinado MA, Moreno V, Germa JR, Capella G, Villanueva A (2006) Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 24:1603–1611PubMedCrossRef Dotor E, Cuatrecases M, Martinez-Iniesta M, Navarro M, Vilardell F, Guino E, Pareja L, Figueras A, Mollevi DG, Serrano T, de Oca J, Peinado MA, Moreno V, Germa JR, Capella G, Villanueva A (2006) Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 24:1603–1611PubMedCrossRef
26.
Zurück zum Zitat Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S, Lenz HJ (2004) A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 91:344–354PubMed Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S, Lenz HJ (2004) A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 91:344–354PubMed
27.
Zurück zum Zitat Lu JW, Gao CM, Wu JZ, Cao HX, Tajima K, Feng JF (2006) Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy. J Hum Genet 51:155–160PubMedCrossRef Lu JW, Gao CM, Wu JZ, Cao HX, Tajima K, Feng JF (2006) Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy. J Hum Genet 51:155–160PubMedCrossRef
28.
Zurück zum Zitat Kawakami K, Graziano F, Watanabe G, Ruzzo A, Santini D, Catalano V, Bisonni R, Arduini F, Bearzi I, Cascinu S, Muretto P, Perrone G, Rabitti C, Giustini L, Tonini G, Pizzagalli F, Magnani M (2005) Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy. Clin Cancer Res 11:3778–3783PubMedCrossRef Kawakami K, Graziano F, Watanabe G, Ruzzo A, Santini D, Catalano V, Bisonni R, Arduini F, Bearzi I, Cascinu S, Muretto P, Perrone G, Rabitti C, Giustini L, Tonini G, Pizzagalli F, Magnani M (2005) Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy. Clin Cancer Res 11:3778–3783PubMedCrossRef
29.
Zurück zum Zitat Marcuello E, Altes A, del Rio E, Cesar A, Menoyo A, Baiget M (2004) Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 112:733–737PubMedCrossRef Marcuello E, Altes A, del Rio E, Cesar A, Menoyo A, Baiget M (2004) Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 112:733–737PubMedCrossRef
30.
Zurück zum Zitat Marcuello E, Altes A, Menoyo A, Rio ED, Baiget M (2006) Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 57:835–840PubMedCrossRef Marcuello E, Altes A, Menoyo A, Rio ED, Baiget M (2006) Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 57:835–840PubMedCrossRef
31.
Zurück zum Zitat Lu JW, Gao CM, Wu JZ, Sun XF, Wang L, Feng JF (2004) Relationship of methylenetetrahydrofolate reductase C677T polymorphism and chemosensitivity to 5-fluorouracil in gastric carcinoma. Ai Zheng 23:958–962PubMed Lu JW, Gao CM, Wu JZ, Sun XF, Wang L, Feng JF (2004) Relationship of methylenetetrahydrofolate reductase C677T polymorphism and chemosensitivity to 5-fluorouracil in gastric carcinoma. Ai Zheng 23:958–962PubMed
Metadaten
Titel
The polymorphisms of TS and MTHFR predict survival of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population
verfasst von
Zhao-Hui Huang
Dong Hua
Li-Hua Li
Publikationsdatum
01.04.2009
Verlag
Springer-Verlag
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 5/2009
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-008-0815-6

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